Adrenocorticotropin, or ACTH, is a hormone that is secreted by the pituitary gland in response to physiological or psychological stress. In response to a signal from corticotrophin-releasing hormone (CRH) that is released in the hypothalamus under stress, ACTH is produced by cleavage of a large precursor molecule, pro-opiomelanocortin (POMC). Secreted. ACTH, then travels to the adrenal cortex, where it binds to and activates melanocortin 2 receptors (MC2Rs) located primarily on the cell surface of adrenocortical cells of the adrenal glands. Activation of MC2R in turn leads to the production of the internal second messenger, cAMP, in the adrenal cell. cAMP binds and activates protein kinase (PKA), which activates enzymes leading to the conversion of the lipid cholesterol to the steroid hormone cortisol.
Cortisol is a vital hormone that affects numerous biological processes in order to restore homeostasis after stress. Some processes regulated by cortisol include regulating glucose homeostasis, increasing blood pressure, gluconeogenesis, promoting metabolism of glycogen, lipids, and proteins, and suppressing the immune system. Under normal physiological conditions, cortisol levels are tightly coordinated. However, in some conditions such as Cushing's Syndrome and chronic stress, cortisol is overproduced. The overproduction of cortisol has been shown to have many negative effects, such as damaging the hippocampus, a region of the brain that is critical for cognitive functions and regulation of the hypothalamus/pituitary/adrenal axis; increasing fat deposits, blood pressure levels, and blood sugar levels; bone loss; muscle weakness; and weakening (suppression) of the immune system.
Accordingly, there is a need for methods of preventing or decreasing ACTH-dependent overproduction of cortisol. The present invention satisfies this need and others.